Microbiota colonization tunes the antigen threshold of microbiota-specific T cell activation in the gut

Harnessing the potential of commensal bacteria for immunomodulatory therapy in the gut requires the identification of conditions that modulate immune activation towards incoming colonizing bacteria. In this study, we used the commensal Bacteroides thetaiotaomicron (B.theta) and combined it with B.theta-specific transgenic T cells, in the context of defined colonization of gnotobiotic and immunodeficiency mouse models, to probe the factors modulating bacteria-specific T cell activation against newly colonizing bacteria. After colonizing germ-free (GF) and conventionally raised (SPF) mice with B.theta, we only observed proliferation of B.theta-specific T cells in GF mice. Using simple gnotobiotic communities we could further demonstrate that T-cell activation against newly colonizing gut bacteria is restricted by previous bacteria colonization in GF mice. However, this restriction requires a functional adaptive immune system as Rag1$^{-/-}$ allowed B.theta-specific T cell proliferation even after previous colonization. Interestingly, this phenomenon seems to be dependent on the type of TCR-transgenic model used. B.theta-specific transgenic T cells also proliferated after gut colonization with an E.coli strain carrying the B.theta-specific epitope. However, this was not the case for the SM-1 transgenic T cells as they did not proliferate after similar gut colonization with an E.coli strain expressing the cognate epitope. In summary, we found that activation of T cells towards incoming bacteria in the gut is modulated by the influence of colonizing bacteria on the adaptive immune system of the host

Metabolic reconstitution of germ-free mice by a gnotobiotic microbiota varies over the circadian cycle.

The capacity of the intestinal microbiota to degrade otherwise indigestible diet components is known to greatly improve the recovery of energy from food. This has led to the hypothesis that increased digestive efficiency may underlie the contribution of the microbiota to obesity. OligoMM12-colonized gnotobiotic mice have a consistently higher fat mass than germ-free (GF) or fully colonized counterparts. We therefore investigated their food intake, digestion efficiency, energy expenditure, and respiratory quotient using a novel isolator-housed metabolic cage system, which allows long-term measurements without contamination risk. This demonstrated that microbiota-released calories are perfectly balanced by decreased food intake in fully colonized versus gnotobiotic OligoMM12 and GF mice fed a standard chow diet, i.e., microbiota-released calories can in fact be well integrated into appetite control. We also observed no significant difference in energy expenditure after normalization by lean mass between the different microbiota groups, suggesting that cumulative small differences in energy balance, or altered energy storage, must underlie fat accumulation in OligoMM12 mice. Consistent with altered energy storage, major differences were observed in the type of respiratory substrates used in metabolism over the circadian cycle: In GF mice, the respiratory exchange ratio (RER) was consistently lower than that of fully colonized mice at all times of day, indicative of more reliance on fat and less on glucose metabolism. Intriguingly, the RER of OligoMM12-colonized gnotobiotic mice phenocopied fully colonized mice during the dark (active/eating) phase but phenocopied GF mice during the light (fasting/resting) phase. Further, OligoMM12-colonized mice showed a GF-like drop in liver glycogen storage during the light phase and both liver and plasma metabolomes of OligoMM12 mice clustered closely with GF mice. This implies the existence of microbiota functions that are required to maintain normal host metabolism during the resting/fasting phase of circadian cycle and which are absent in the OligoMM12 consortium

Author Correction: A consensus-based transparency checklist.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria, present unique challenges to energetic homeostasis by disrupting energy-producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut)–type methylmalonic aciduria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared with littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator–activated receptor and Fgf21-controlled pathways. Together, these shed light on the mechanisms and adaptations behind energy imbalance in methylmalonic aciduria and provide insight into metabolic responses to chronic energy shortage, which may have important implications for disease understanding and patient management

A consensus-based transparency checklist

We present a consensus-based checklist to improve and document the transparency of research reports in social and behavioural research. An accompanying online application allows users to complete the form and generate a report that they can submit with their manuscript or post to a public repository

Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria (MMAuria), present unique challenges to energetic homeostasis by disrupting energy producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut) type MMAuria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared to littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these indicate hypometabolism, energetic inflexibility and increased stores at the expense of active tissue as energy shortage consequences

Growing, evolving and sticking in a flowing environment: understanding IgA interactions with bacteria in the gut

Immunology research in the last 50 years has made huge progress in understanding the mechanisms of anti-bacterial defense of deep, normally sterile, tissues such as blood, spleen and peripheral lymph nodes. In the intestine, with its dense commensal microbiota, it seems rare that this knowledge can be simply translated. Here we put forward the idea that perhaps it is not always the theory of immunology that is lacking to explain mucosal immunity, but rather that we have overlooked crucial parts of the mucosal immunological language required for its translation: namely intestinal and bacterial physiology. We will try to explain this in the context of intestinal secretory antibodies (mainly secretory IgA), which have been described to prevent, to alter, to not affect, or to promote colonization of the intestine and gut-draining lymphoid tissues, and where effector mechanisms have remained elusive. In fact, these apparently contradictory outcomes can be generated by combining the basic premises of bacterial agglutination with an understanding of bacterial growth (i.e. secretory IgA-driven enchained growth), fluid handling and bacterial competition in the gut lumen

“EvoVax” – A rationally designed inactivated Salmonella Typhimurium vaccine induces strong and long-lasting immune responses in pigs

Salmonella enterica subspecies enterica serovar Typhimurium (S.Tm) poses a considerable threat to public health due to its zoonotic potential. Human infections are mostly foodborne, and pork and pork products are ranked among the top culprits for transmission. In addition, the high percentage of antibiotic resistance, especially in monophasic S.Tm, limits treatment options when needed. Better S.Tm control would therefore be of benefit both for farm animals and for safety of the human food chain. A promising pre-harvest intervention is vaccination. In this study we tested safety and immunogenicity of an oral inactivated S.Tm vaccine, which has been recently shown to generate an "evolutionary trap" and to massively reduce S.Tm colonization and transmission in mice. We show that this vaccine is highly immunogenic and safe in post-weaning pigs and that administration of a single oral dose results in a strong and long-lasting serum IgG response. This has several advantages over existing - mainly live - vaccines against S.Tm, both in improved seroconversion and reduced risk of vaccine-strain persistence and reversion to virulence

Missed opportunities for HIV control: Gaps in HIV testing for partners of people living with HIV in Lima, Peru.

Based on the hypothesis that HIV programs struggle to deliver health services that harmonize necessities of treatment and prevention, we described the outcomes of routinely provided HIV testing to partners of people living with HIV (PLWH) through a secondary analysis of routine data collected at a public hospital in Lima, Peru.Among PLWH enrolled in the study center's HIV program between 2005 and 2014, we identified index cases (IC): PLWH who reported a unique partner not previously enrolled. We grouped partners according to their HIV status as reported by IC and collected data on HIV testing, clinical characteristics and admissions. The main outcome was the frequency of HIV testing among partners with reported unknown/seronegative HIV status.Out of 1586 PLWH who reported a unique partner at enrollment, 171 had a previously enrolled partner, leaving 1415 (89%) IC. HIV status of the partner was reported as unknown in 571 (40%), seronegative in 325 (23%) and seropositive in 519 (37%). Out of 896 partners in the unknown/seronegative group, 72 (8%) had HIV testing, 42/72 (58%) tested within three months of IC enrollment. Among the 49/72 (68%) who tested positive for HIV, 33 (67%) were enrolled in the HIV program. The proportion in WHO clinical stage IV was lower in enrolled partners compared to IC (37% vs 9%, p = 0.04). Non-tested partners (824) were likely reachable by the hospital, as 297/824 (36%) of their IC were admitted in the study center at least once, 51/243 (21%) female IC had received pregnancy care at the study center, and 401/692 (64%) of IC on antiretroviral therapy had achieved viral suppression, implying frequent visits to the hospital for pill pick-up.In this setting, HIV testing of partners of PLWH was suboptimal, illustrating missed opportunities for HIV control. Integration of HIV strategies in primarily clinical-oriented services is a challenging need